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J Neurol Neurosurg Psychiatry. 2020 Mar;91(3):263-270. doi: 10.1136/jnnp-2019-321954. Epub 2020 Jan 14.

Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia.

Author information

1
UK Dementia Research Institute, Department of Neurodegenerative Disease, University College London, London, UK.
2
Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
3
Centre for Medical Image Computing, University College London, London, UK.
4
Neuradiological Academic Unit, UCL Queen Square Institute of Neurology, London, UK.
5
Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands.
6
Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, País Vasco, Spain.
7
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain.
8
Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
9
Clinique Interdisciplinaire de Mémoire du CHU de Québec, Département des Sciences Neurologiques, Université Laval, Québec, Québec, Canada.
10
Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
11
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
12
Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
13
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Centro Dino Ferrari, Milan, Italy.
14
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
15
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
16
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada.
17
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
18
German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
19
Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
20
Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
21
Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milan, Italy.
22
Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
23
Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada.
24
Department of Clinical Neurology, University of Oxford, Oxford, UK.
25
Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
26
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
27
Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.
28
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
29
IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
30
Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy.
31
Department of Neurology, University of Ulm, Ulm, Germany.
32
Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
33
Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK j.rohrer@ucl.ac.uk.

Abstract

BACKGROUND:

There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker.

METHODS:

Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman's correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures.

RESULTS:

Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, -61.3 to 54.6), MAPT mutations (12.7, -33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe.

CONCLUSIONS:

Raised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.

PMID:
31937580
DOI:
10.1136/jnnp-2019-321954

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